An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Nese Direk, Stephanie Williams, Jennifer A Smith, Stephan Ripke, Tracy Air, Azmeraw T Amare, Najaf Amin, Bernhard T Baune, David A Bennett, Douglas H R Blackwood, Dorret Boomsma, Gerome Breen, Henriette Nørmølle Buttenschøn, Enda M Byrne, Anders D Børglum, Enrique Castelao, Sven Cichon, Toni-Kim Clarke, Marilyn C Cornelis, Udo DannlowskiPhilip L De Jager, Ayse Demirkan, Enrico Domenici, Cornelia M van Duijn, Erin C Dunn, Johan G Eriksson, Tonu Esko, Jessica D Faul, Luigi Ferrucci, Myriam Fornage, Eco de Geus, Michael Gill, Scott D Gordon, Hans-Jörgen Grabe, Gerard van Grootheest, Steven P Hamilton, Catharina A Hartman, Andrew C Heath, Karin Hek, Albert Hofman, Georg Homuth, Carsten Horn, Jouke Jan Hottenga, Sharon L R Kardia, Stefan Kloiber, Karestan Koenen, Zoltán Kutalik, Karl-Heinz Ladwig, Jari Lahti, Douglas F Levinson, Cathryn M Lewis, Glyn Lewis, Qingqin S Li, David J Llewellyn, Susanne Lucae, Kathryn L Lunetta, Donald J MacIntyre, Pamela A F Madden, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Yuri Milaneschi, Grant W Montgomery, Ole Mors, Thomas H Mosley, Joanne M Murabito, Bertram Müller-Myhsok, Markus M Nöthen, Dale R Nyholt, Michael C O'Donovan, Brenda W Penninx, Michele L. Pergadia, Roy Perlis, James B Potash, Martin Preisig, Shaun M Purcell, Jorge A Quiroz, Katri Räikkönen, John P Rice, Marcella Rietschel, Margarita Rivera, Thomas G Schulze, Jianxin Shi, Stanley I Shyn, Grant C Sinnamon, Johannes H Smit, Jordan W Smoller, Harold Snieder, Toshiko Tanaka, Katherine E Tansey, Alexander Teumer, Rudolf Uher, Daniel Umbricht, Sandra Van der Auwera, Erin B Ware, David R Weir, Myrna M Weissman, Gonneke Willemsen, Jingyun Yang, Wei Zhao, Henning Tiemeier, Patrick F Sullivan

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Abstract

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.

METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.

RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10(-9)).

CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Original languageEnglish
Pages (from-to)322-329
Number of pages8
JournalBiological Psychiatry
Volume82
Issue number5
DOIs
Publication statusPublished - 1 Aug 2017

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Direk, N., Williams, S., Smith, J. A., Ripke, S., Air, T., Amare, A. T., ... Sullivan, P. F. (2017). An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. Biological Psychiatry, 82(5), 322-329. https://doi.org/10.1016/j.biopsych.2016.11.013